In December 2013, a World Health Organization press release reported a sharp rise in breast cancer worldwide with 1.7 million women diagnosed. Despite significant efforts to reduce these numbers, breast cancer is still the most common malignancy in women and the most common cause of cancer death. This is true in the U.S., where women have a 12.3%, or 1 in 8, lifetime risk of being diagnosed with breast cancer. The development of breast cancer is complex since many factors contribute to the disease, including intrinsic cell factors, microenvironment, angiogenesis and tumor-specific immune responses. A better understanding of the pathophysiological background of breast cancer is required for the development of improved risk assessments, targeted therapies, and individualized treatment strategies for patients. In this regard, expression of a new factor, interferon regulatory factor 5 (IRF5), in human breast tumors was recently identified to be associated with increased survival and lower incidence of metastasis. Given that metastasis of primary breast cancer to distant sites and recurrence to incurable disease are the main causes of fatalities, identification of new factors that contribute to these processes are critically important to our understanding of disease risk and progression. Originally recognized as an important regulator of immune responses, IRF5 has subsequently been shown to mediate tumorigenesis in multiple tumor types. Using a mouse model of spontaneous mammary tumorigenesis, precancerous hyperproliferative lesions have been identified in mice lacking the Irf5 gene. Over time, 40% of Irf5-/- mice developed spontaneous mammary tumors as compared to wild-type littermates. Preliminary data also indicate that spontaneous mammary tumor development is gender-dependent since only female Irf5-/- mice, and not male, developed disease, suggesting a hormonal effect on IRF5. Together, these data support a causal role for IRF5 in breast tumor initiation and progression. Based on these findings, we hypothesize that loss of Irf5 in a murine model of mammary tumorigenesis enhances spontaneous tumor formation in a hormone-dependent manner involving both its growth regulatory and immunoregulatory functions. This hypothesis will be tested in the following Specific Aims: 1) Expansion of mouse cohorts to include female and male matched Irf5+/+, Irf5+/- and Irf5-/- littermate mice for analysis of gender-dependent tumor formation and mammary gland development, 2) Identification of the mechanism(s) by which loss of Irf5 contributes to spontaneous mammary tumorigenesis, and 3) Generation of an in vivo transplant model that enables distinction between IRF5 tumor suppressor function in mammary epithelial cells and its role in the lymphoid system. Results from this study will provide clear and specific insight into IRF5 expression and function(s) in mammary gland development and mammary epithelial cell growth, that in the future, will lead to new prognostic markers for breast cancer risk, recurrence or progression to invasive cancer, as well as new therapeutic avenues for inhibiting disease progression and recurrence.